Movement disorders are a group of central nervous system conditions and/or diseases in which the control of movement is altered with relative preservation of strength, muscle bulk, and mechanical range of motion. They include those diseases which either involve an excess of movement or with a paucity of voluntary and automatic movements. Thus, the movement disorders can be divided into hyperkinesias (excessive movements), dyskinesias (unnatural movements), hypokinesias (paucity of movements), and abnormal involuntary movements.
Hyperkinetic movement disorders (also known as hyperkinesia) imply an increase in muscular activity that can result in excessive movements, either normal, or abnormal movements, or a combination of both.
The hyperkinetic movements can be defined as a wide array of movement disorders characterized by excessive repetitive or sporadic involuntary movements. The most frequently hyperkinetic symptoms are, among others, ataxia, athetosis, chorea, dystonia, ballismus, hemifacial spasm, myoclonus, stereotypes, tardive dystonia, tics, and tremors. The movements can be rhythmic, discrete, repeated, and/or random. The specific pathophysiology of these disorders is diverse although many hyperkinetic movements are the result of improper regulation of the basal ganglia-thalamocortical circuitry.
Each disorder can feature one or more hyperkinetic movements as prominent symptoms, for example in disorders like Huntington's disease, tardive dyskinesia and Tourette syndrome.
Huntington's disease (HD) is a dominantly inherited neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. HD is due to mutations in the gene encoding for huntingtin, and it is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington's chorea. Thus, the term “Huntington's disease” and “Huntington's chorea” have the same meaning and are used interchangeable. The most prominent early effects in HD are in a part of the basal ganglia called the neostriatum, which is composed of the caudate nucleus and putamen. Symptoms of the disease can vary between individuals, but usually progress predictably. The earliest symptoms are often subtle problems with mood or cognition, followed by a general lack of coordination and an unsteady gait. In advanced stages of the disease, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities, as well as behavioural and psychiatric problems. Physical abilities are gradually impeded until coordinated movement becomes very difficult, and mental abilities generally decline into dementia. Although the genetic basis of the pathology is well known there is not yet a cure for HD. The pharmacological and non-pharmacological treatments disclosed in the state of the art are focused in minimizing the symptoms of the disease, mainly in relieving the hyperkinetic movements associated to HD.
Tourette syndrome (TS) is a neurologic disorder manifested by motor and vocal or phonic tics usually starting during childhood and often accompanied by some comorbid behavioural problems such as obsessive-compulsive disorder or attention-deficit hyperactivity disorder. Tics are defined as involuntary, sudden, rapid, recurrent, non-rhythmic movement (motor tics) and vocalisations (vocal or phonic tics). The cause of TS is yet unknown, but the disorder appears to be inherited in the majority of patients, as shown by early family studies. Little is known about the exact brain mechanisms associated with tic development and expression, although preliminary evidence from neurochemical and neuroimaging investigations suggests a primary role for dysfunction of the dopaminergic pathways within the cortico-striato-cortico-frontal circuitry. Treatment of TS includes both pharmacotherapy and cognitive behavioural treatment.
Tardive dyskinesia (TD) is a disorder characterized by involuntary, repetitive body movements and is the result of treatment with dopamine receptor-blocking agents. The principal site affected by classic TD is the face, particularly around the mouth, typically called oral-buccal-facial dyskinesia. The limbs and trunk are affected less often than the mouth. The TD syndromes tend to appear late in the course of treatment, hence the term tardive. The symptoms can occur when the patient is taking these drugs or within a period of time after stopping the treatment.
The restless legs syndrome (RLS) is characterized by a deep, ill-defined discomfort or dysesthesia in the legs, which arises during prolonged rest, or when the patient is drowsy and trying to fall asleep, especially at night. The most commonly associated medical condition is iron deficiency although there is also evidence to suggest that the disorder in many if not most patients is transmitted as an autosomal dominant trait.
Wilson's disease is an inborn error of copper metabolism manifest as hepatic cirrhosis and basal ganglia damage. The condition is due to mutations in the Wilson disease protein (ATP7B) gene and the initial manifestations of the illness are neurologic in about 40% of patients. The pathologic abnormalities in the brain are primarily in the basal ganglia, with cavitary necrosis of the putamen and caudate, associated with neuronal loss, axonal degeneration and astrocytosis. In addition, there is cortical atrophy.
One of the pharmacological symptomatic treatments of the hyperkinetic movement disorders disclosed in the state of the art is based on the administration of an inhibitor of the vesicular monoamine transporter 2 (VMAT2). In the striatum, VMAT2 mainly transports dopamine from cellular cytosol into synaptic vesicles from dopaminergic neurons, protecting it from auto-oxidization in the presence of oxygen radicals. Thus, inhibition of VMAT2 reduces the uptake of dopamine into the synaptic vesicles resulting in an overall reduction in total dopamine.
In particular, tetrabenazine ((SS,RR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one) is a selective inhibitor of the monoamine transporter VMAT2 which blocks the transport of dopamine to the presynaptic neuronal vesicles, impairing its release to the synaptic cleft. Tetrabenazine is a reversible inhibitor of VMAT2, and the approved drug for the symptomatic treatment of chorea associated to Huntington's disease, tardive dyskinea, and Tourette syndrome, as well as for symptoms like hemiballismus.
Unfortunately, tetrabenazine has a poor and variable bioavailability, being also extensively metabolised by first-pass metabolism. Additionally, tetrabenazine has a black-box warning because of an increase in depression and suicidality, as well as the potential to cause Parkinsonism and Neuroleptic Malignant Syndrome.
Despite all the research efforts invested in the past, the prophylaxis and/or treatment of hyperkinetic movement disorders is far from being satisfactory. Therefore, there is a high unmet need for a safe and effective treatment for those disorders.